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Expression of human apolipoprotein E4 reduces insulin-receptor substrate 1 expression and Akt phosphorylation in the ageing liver.

Ong QR, Chan ES, Lim ML, Wong BS - FEBS Open Bio (2014)

Bottom Line: We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function.Liver cholesterol was not affected.These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

ABSTRACT
The diabetic drug rosiglitazone was reported to improve glucose tolerance in insulin-resistant ApoE3 but not ApoE4 knock-in mice. We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function. At 12 weeks, no difference in liver insulin signaling was detected between fasting ApoE3 and ApoE4 mice. At 72 weeks however, ApoE4 mice had lower IRS-1 and PI3K expression, and reduced Akt phosphorylation. This decline was associated with lower insulin and higher glucose in ApoE4 mouse liver. Liver cholesterol was not affected. These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

No MeSH data available.


Akt expression and phosphorylation in the liver of fasting ApoE mice. (A) Immunoblotting of total Akt, phosphorylated Akt (S473) and phosphorylated Akt (T308) in the liver of ApoE3 and ApoE4 mice at 12 and 72 weeks of age. β-actin was immunoblotted to ensure similar gel loading of the starting material in each sample. The blot is a representative of three independent experiments. Densitometry analysis of (B) total Akt level relative to β-actin level, (C) phosphorylated Akt(S437) and (D) phosphorylated Akt(T308) level relative to total Akt level, in 12 and 72 weeks old ApoE3 (white bar) and ApoE4 (grey bar) mice was performed using the NIH ImageJ software. Each value represents the mean ± SEM for individual mouse liver sample (n = 3 at each time point for each mouse line). Lower Akt phosphorylation at S473 and T308 were detected in 72 weeks ApoE4 mice as compared to ApoE3 mice at similar age. (∗p < 0.02; ∗∗p < 0.04, using Student’s t-test.)
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f0010: Akt expression and phosphorylation in the liver of fasting ApoE mice. (A) Immunoblotting of total Akt, phosphorylated Akt (S473) and phosphorylated Akt (T308) in the liver of ApoE3 and ApoE4 mice at 12 and 72 weeks of age. β-actin was immunoblotted to ensure similar gel loading of the starting material in each sample. The blot is a representative of three independent experiments. Densitometry analysis of (B) total Akt level relative to β-actin level, (C) phosphorylated Akt(S437) and (D) phosphorylated Akt(T308) level relative to total Akt level, in 12 and 72 weeks old ApoE3 (white bar) and ApoE4 (grey bar) mice was performed using the NIH ImageJ software. Each value represents the mean ± SEM for individual mouse liver sample (n = 3 at each time point for each mouse line). Lower Akt phosphorylation at S473 and T308 were detected in 72 weeks ApoE4 mice as compared to ApoE3 mice at similar age. (∗p < 0.02; ∗∗p < 0.04, using Student’s t-test.)

Mentions: We next determined if the aberrant IRS1 and PI3K expression (Fig. 1) affects downstream Akt expression and phosphorylation (Fig. 2). Liver Akt expression did not differ between ApoE3 and ApoE4 mice at 12 weeks and at 72 weeks (Fig. 2B). Akt phosphorylation at Serine-473 (S473) and at Threonine-308 (T308) were also unaffected in 12 weeks old ApoE3 and ApoE4 mice (Fig. 2A).


Expression of human apolipoprotein E4 reduces insulin-receptor substrate 1 expression and Akt phosphorylation in the ageing liver.

Ong QR, Chan ES, Lim ML, Wong BS - FEBS Open Bio (2014)

Akt expression and phosphorylation in the liver of fasting ApoE mice. (A) Immunoblotting of total Akt, phosphorylated Akt (S473) and phosphorylated Akt (T308) in the liver of ApoE3 and ApoE4 mice at 12 and 72 weeks of age. β-actin was immunoblotted to ensure similar gel loading of the starting material in each sample. The blot is a representative of three independent experiments. Densitometry analysis of (B) total Akt level relative to β-actin level, (C) phosphorylated Akt(S437) and (D) phosphorylated Akt(T308) level relative to total Akt level, in 12 and 72 weeks old ApoE3 (white bar) and ApoE4 (grey bar) mice was performed using the NIH ImageJ software. Each value represents the mean ± SEM for individual mouse liver sample (n = 3 at each time point for each mouse line). Lower Akt phosphorylation at S473 and T308 were detected in 72 weeks ApoE4 mice as compared to ApoE3 mice at similar age. (∗p < 0.02; ∗∗p < 0.04, using Student’s t-test.)
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f0010: Akt expression and phosphorylation in the liver of fasting ApoE mice. (A) Immunoblotting of total Akt, phosphorylated Akt (S473) and phosphorylated Akt (T308) in the liver of ApoE3 and ApoE4 mice at 12 and 72 weeks of age. β-actin was immunoblotted to ensure similar gel loading of the starting material in each sample. The blot is a representative of three independent experiments. Densitometry analysis of (B) total Akt level relative to β-actin level, (C) phosphorylated Akt(S437) and (D) phosphorylated Akt(T308) level relative to total Akt level, in 12 and 72 weeks old ApoE3 (white bar) and ApoE4 (grey bar) mice was performed using the NIH ImageJ software. Each value represents the mean ± SEM for individual mouse liver sample (n = 3 at each time point for each mouse line). Lower Akt phosphorylation at S473 and T308 were detected in 72 weeks ApoE4 mice as compared to ApoE3 mice at similar age. (∗p < 0.02; ∗∗p < 0.04, using Student’s t-test.)
Mentions: We next determined if the aberrant IRS1 and PI3K expression (Fig. 1) affects downstream Akt expression and phosphorylation (Fig. 2). Liver Akt expression did not differ between ApoE3 and ApoE4 mice at 12 weeks and at 72 weeks (Fig. 2B). Akt phosphorylation at Serine-473 (S473) and at Threonine-308 (T308) were also unaffected in 12 weeks old ApoE3 and ApoE4 mice (Fig. 2A).

Bottom Line: We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function.Liver cholesterol was not affected.These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

ABSTRACT
The diabetic drug rosiglitazone was reported to improve glucose tolerance in insulin-resistant ApoE3 but not ApoE4 knock-in mice. We therefore examined whether apolipoprotein E (ApoE) has genotype-specific effects on liver insulin function. At 12 weeks, no difference in liver insulin signaling was detected between fasting ApoE3 and ApoE4 mice. At 72 weeks however, ApoE4 mice had lower IRS-1 and PI3K expression, and reduced Akt phosphorylation. This decline was associated with lower insulin and higher glucose in ApoE4 mouse liver. Liver cholesterol was not affected. These results show that ApoE4 expression reduces liver insulin signaling and insulin levels, leading to higher glucose content.

No MeSH data available.